The KRAB-zinc-finger protein ZFP708 mediates epigenetic repression at RMER19B retrotransposons.

Michelle K Y Seah,Ei Leen Leong,Slim Mzoughi,Wen Jun Peh,Diana H P Loh,Ernesto Guccione,Brenda Y Han,Todd S Macfarlan,Yaju Wang,Gernot Wolf,Pierre-Alexis Vincent Goy,Heike Wollmann,Daniel M Messerschmidt,Hui Mun Loh,Esther Wong

doi:10.1242/dev.170266

Abstract

ABSTRACTGlobal epigenetic reprogramming is vital to purge germ cell-specific epigenetic features to establish the totipotent state of the embryo. This process transpires to be carefully regulated and is not an undirected, radical erasure of parental epigenomes. The TRIM28 complex has been shown to be crucial in embryonic epigenetic reprogramming by regionally opposing DNA demethylation to preserve vital parental information to be inherited from germline to soma. Yet the DNA-binding factors guiding this complex to specific targets are largely unknown. Here, we uncover and characterize a novel, maternally expressed, TRIM28-interacting KRAB zinc-finger protein: ZFP708. It recruits the repressive TRIM28 complex to RMER19B retrotransposons to evoke regional heterochromatin formation. ZFP708 binding to these hitherto unknown TRIM28 targets is DNA methylation and H3K9me3 independent. ZFP708 mutant mice are viable and fertile, yet embryos fail to inherit and maintain DNA methylation at ZFP708 target sites. This can result in activation of RMER19B-adjacent genes, while ectopic expression of ZFP708 results in transcriptional repression. Finally, we describe the evolutionary conservation of ZFP708 in mice and rats, which is linked to the conserved presence of the targeted RMER19B retrotransposons in these species.

Highlights

The inheritance of selective epigenetic information from germline to soma is crucial for organismal development
We show here that ZFP708 is needed to carry over DNA methylation at RMER19B long terminal repeat (LTR)-retrotransposons from germline to soma, expanding our understanding of the KRABZFP/TRIM28-protected heritable epigenome
Zfp708 is highly expressed in oocytes and zygotes, but RNA levels drastically decrease at the two-cell stage and remain low or undetectable in subsequent preimplantation stages, including the ICM of the blastocyst (Fig. 1A)

Summary

Introduction

The inheritance of selective epigenetic information from germline to soma is crucial for organismal development. This epigenetic memory is remarkably maintained during the near-complete erasure of the germ cell epigenomes that establishes the totipotent embryonic state. The mechanisms mediating this resistance to reprogramming are far from understood. At genomic imprints, which are paradigmatic for epigenetic inheritance, DNMT1 is recruited directly or indirectly through TRIM28, which is in turn directed to specific genomic loci by the DNA-binding protein ZFP57 (Li et al, 2008; Messerschmidt et al, 2012; Quenneville et al, 2011). ZFP57 is a Krueppel-associated box (KRAB) domain zinc-finger protein (ZFP)

Methods

Results

Conclusion